Dextrorotatory kynurenine suppresses acute rejection through inhibiting M1 macrophage-mediated inflammation

Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating immunosuppression was poorly depicted. To address this, serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17β-chloroformate (17β-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from the GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Through analysis of patient serum and murine transplantation models, we identified D-Kyn as a key metabolite whose elevated levels correlate with stable graft function. We found that D-Kyn, more effectively than its chiral counterpart L-Kyn, inhibits the inflammatory activity of M1 macrophages. This suppression is mediated via the PHGDH/TLR4/Caspase-1 pathway, reducing the transcription and secretion of inflammatory cytokines. In murine models of skin and kidney transplantation, D-Kyn treatment demonstrated potent immunosuppressive effects, attenuating macrophage-mediated inflammation and CD8 + T cell activation, potentially through regulation of macrophage-derived IL-23a. Our findings reveal D-Kyn as a promising therapeutic candidate for preventing acute rejection and improving transplant outcomes and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.